Combination therapy treatment for viral infections

Abstract

Therapeutics which employ a combination of an antiviral agent and an EP4 receptor agonist for the treatment of human respiratory diseases associated with viral infections are described. Viral infections may include an influenza A virus, for example H1N1, H3N2 and H5N1, and mutations thereof, and/or a coronavirus, for example a virus that causes severe acute respiratory syndrome, “SARS”.

1 . A method for treating a viral disease, the method comprising administering to a patient in need thereof an antiviral agent in combination with an EP4 receptor agonist. 
     
     
         2 . The method of  claim 1 , wherein at least one of the EP4 receptor agonist and the antiviral agent is administered at a suboptimal dosage. 
     
     
         3 . The method of  claim 2 , wherein the EP4 receptor agonist is administered at between about 10% and about 100% of the median of the range of optimal dosage for a given patient. 
     
     
         4 . The method of  claim 2 , wherein the antiviral agent is administered at between about 10% and about 80% of the optimal dosage for a given patient. 
     
     
         5 . The method of  claim 3 , wherein the antiviral agent is administered at between about 15% and about 50% of the optimal dosage for the given patient. 
     
     
         6 . The method of  claim 1 , wherein the viral disease is caused by an influenza virus. 
     
     
         7 . The method of  claim 1 , wherein the viral disease is caused by a corona virus. 
     
     
         8 . The method of  claim 1 , wherein the patient is a human. 
     
     
         9 . The method of  claim 1 , wherein the antiviral agent is selected from a viral protein M2 ion channel inhibitor, a neuraminidase inhibitor, an RNA replication and translation inhibitor and a polymerase inhibitor. 
     
     
         10 . The method of  claim 1 , wherein the antiviral agent is amantadine or rimantadine. 
     
     
         11 . The method of  claim 1 , wherein the antiviral agent is oseltamivir, zanamivir, peramivir or {(4S,5R,6R)-5-acetamido-4-guanidino-6-R1R,2R)-2-hydroxy-1-methoxy-3-(octanoyloxy)propyl]-5,6-dihydro-4H-pyran-2-carboxylic acid. 
     
     
         12 . The method of  claim 1 , wherein the antiviral agent is ribavirin. 
     
     
         13 . The method of  claim 1 , wherein the antiviral agent is 6-fluoro-3-hydroxy-2-pyrazinecarboxamide. 
     
     
         14 . The method of  claim 1 , wherein the EP4 receptor agonist is beraprost sodium, (+)-[1R,2R,3aS,8bS]-2,3,3a,8b-tetrahydro-2-hydroxyl-1-[(E)-(3S)-3-hydroxyl-4-methyl-1-octen-6-ynyl)-1H-cyclopenta[b]benzofuran-5-butanoic acid, sodium salt, (+)-[1R,2R,3aS,8bS]-2,3,3a,8b-tetrahydro-2-hydroxyl-1-[(E)-(3S, The method of  claim 1 , further including coadministering (R)-2-amino-4-(4-heptyloxyphenyl)-2-methylbutanol. 
     
     
         15 . The method of  claim 1 , further including coadministering pioglitazone or rosiglitazone. 
     
     
         16 . The method of  claim 1 , wherein the EP4 agonist is 4R)-3-hydroxyl-4-methyl-1-octen-6-ynyl)-1H-cyclopenta[b]benzofuran-5-butanoic acid, sodium salt, (+)-[1R,2R,3aS,8bS]-2,3,3a,8b-tetrahydro-2-hydroxyl-1-[(E)-(3S,4S)-3-hydroxyl-4-methyl-1-octen-6-ynyl)-1H-cyclopenta[b]benzofuran-5-butanoic acid, sodium salt or (+)-[1R,2R,3aS,8bS]-2,3,3a,8b-tetrahydro-2-hydroxyl-1-[(E)-(3S)-3-hydroxyl-4-methyl-1-octen-6-ynyl)-1H-cyclopenta[b]benzofuran-5-butanoic acid, sodium salt. 
     
     
         17 . The method of  claim 1 , wherein the EP4 receptor agonist is nileprost, (E)-5-cyano-5-[(1S,5R,6R,7R)-7-hydroxy-6-[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octenyl]-2-oxa-bicyclo[3.3.0]octan-3-yliden]pentanoic acid and isomers (E)-5-cyano-5-[(1S,5R,6R,7R)-7-hydroxy-6-[(E)-(3S,4S)-3-hydroxy-4-methyl-1-octenyl]-2-oxa-bicyclo[3.3.0]octan-3-yliden]pentanoic acid or (E)-5-cyano-5-[(1S,5R,6R,7R)-7-hydroxy-6-[(E)-(3S,4R)-3-hydroxy-4-methyl-1-octenyl]-2-oxa-bicyclo[3.3.0]octan-3-yliden]pentanoic acid or (E)-[(3aR,4R,5R,6aS)-hexahydro-5-hydroxy-4-[(1E,3S)-3-hydroxy-4-methyl-1-octenyl]-2H-cyclopenta[b]furan-2-ylidene]-1H-tetrazole-5-2E-pentanenitrile. 
     
     
         18 . The method of  claim 1 , wherein the EP4 receptor agonist is 
       
         
           
           
               
               
           
         
       
     
     
         19 . The method of  claim 1 , wherein the antiviral agent and the EP4 receptor agonist are administered either in combination or adjunctively with an anti-inflammatory agent. 
     
     
         20 . The method of  claim 19 , wherein the anti-inflammatory agent is an NSAID. 
     
     
         21 . The method of  claim 19 , wherein the anti-inflammatory agent is a steroid. 
     
     
         22 . A pharmaceutical composition comprising an EP4 receptor agonist and an antiviral agent, in a single dosage form, with one or more pharmaceutically acceptable excipients. 
     
     
         23 . A kit comprising a pharmaceutical formulation comprising an antiviral agent and an EP4 receptor agonist. 
     
     
         24 . A kit comprising a first pharmaceutical formulation comprising an antiviral agent and a second pharmaceutical formulation comprising an EP4 receptor agonist. 
     
     
         25 . A combination of an EP4 receptor agonist and an antiviral for use in the treatment of an infection in a human by an influenza virus and/or a corona virus.